JPH03220195A - Substitution of 3-fluorosulfonyloxyceph-3-em - Google Patents

Abstract

NEW MATERIAL: A compound of formula I (Z is S, O, sulfoxide, sulfone or methylene; Q is H, an amino-protecting group, etc.; P is H, a carboxyl-protecting group or a physiologically hydrolyzable ester).

EXAMPLE: 7-Phenoxyacetamido-3-[(fluorosulfonyl)oxy]-ceph-3-em-4-carboxylic acid.

USE: Antibiotics.

PROCESS: A compound of formula II (L is fluorosulfonyloxy, etc.), is reacted with an organotin compound of the formula, R¹-Sn-(R²)₃ (R¹ is H, 2-6C alkenyl, etc.; R² is an organic group) in an inert protonic solvent in the presence of 1-10 mol.% of a Pd(II) or Pd(0) catalyst.

COPYRIGHT: (C)1991,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a method for producing cephem, carba(decia)cephem, and oxa(decia)cephem compounds, and
The present invention relates to 3-(fluorosulfonylonoxy-substituted cephems and carba t-fem intercontaminants useful in the manufacturing process.

[Conventional technology]

Hoahs et al.'s US patent! No. 4,520.022 (1
Published on May 28, 1985), the following formula [where g+ and R2 are H, OH, OCH, or C
Cephalosporin antibiotics with a Vc1-propenyl group in the 3-position represented by [1] have been described.

The 1-propenyl group of the compound of Ho5hi et al. is (E)
The CZ) form is preferable because its antibacterial activity is increased compared to the CZ form. These compounds are 3-no-romethyl-
A cephalosporin is prepared by reacting with a triarylphosphine to produce a phosphoranyl intermediate and then treating this intermediate with an aldehyde to form a propenyl or substituted propenyl group.

The above method gives a mixture of cis<Z)- and trans(A')-isomers and requires expensive separation and processing conditions to obtain the preferred 1/XCZ> isomer, which is more antibacterially active. adjustment is required. The overall yield of the desired cis-CZ)-isomer based on the starting material is therefore lower than the trans-CZ
E) - decreases by the amount of isomer.

More recently, palladium contact coupling method has been developed.
In order to avoid the formation of undesired isomers and improve the yield, it was applied to the generation of alkenyl substituents at the 3-position of the cephalosporin nucleus. Pd(O) compound, metal
The allylic coupling of 3-7-lomethylcepheme with vinyltin under the influence of i6 and tris-(2-furyl)phosphine led to the preparation of novel cephalosporins [S, R, Eahar et al. 1) U.S. Patent Nos. 4 and 8
No. 47.373 (patented July 11, 1989).

The coupling of cyclohexenyl triflate and vinyl tributyltin using a Pd(O) compound/Licl medium is 3-driphlogycef-3-Mco(z)-
Various types of 3 by reaction with 1-benyl-tributyltin
- U.S. Pat. No. 4,870,168 (September 26, 1989) to CS, R, Hxktr et al. for the production of [(Z)-1-propenyl)cef-3-em].

Further research on reaction scope and optimization of palladium catalytic reaction conditions between vinyl truffle V-1 and vinyl tin is available at 5.
cott and 5till-J, Aar, Chat
n, Soc, 108°3033-3040 (1986)
; and: 5tiLl and Groh J, Amar
, Cham, Soc, 109 + 813-81
7 (1987).

3-trifuxicef-3-em in the presence of PdC1t(CHsCi'J)2 without the phosphine reagent or LiC1 as also required by the method of W.J.5eott et al. (op, eit). and organic tributyl i
Coupling with reagent is 196th le n5rtcas
CheniecL 5ociety Nationa
lMaatin (B Los Angeles, September 1988)
Month 25th to 30th, Diviaio% of Orgαn
In ic Ckgrnsstry 432, G.
Reported by Cook and J, H, McDonaLd III.

[Summary of the invention]

The present invention provides novel 3-(fluorosulfonyl)oxy-substituted cephems, oxacephems and carbacephems having the following formula (I).

t, ;utr (υ [wherein, Z is sulfur, *cumulative, sulfoquinodo, sulfo/
, 1γ is methylene: Q is 7Ki, ? The amine protecting group, which may be used in the synthesis of phalosboringo and hardware; 1 is the acyl group of the commonly used 7-azilaminophalosporin antibiotic; and P is hydrogen, attached to cephalosporinization. The present invention also relates to cephems having an alkenyl, alkynyl, aryl, or heterocyclic group at the 3-position of the cephems, We also provide instructions for Oxacefem, S and Carbacefem.

The process consists of reacting a 3-sulfonyloxy substituted cephem, oxacephem, or carbacephem reagent with an organotin compound in the presence of a Pd- or Pd(O) catalyst. The 3-sulfonyloxy groups mentioned above are a fluorosulfonyloxy group, a 4-nitrobenzenesulfonyloxy group, and a 4-bromobenzenesulfonyloxy group. The method of the present invention is disclosed in Japanese Patent No. 4,870.1.
No. 68 represents a significant improvement over that patent in that the expensive reagent 3-trifloxycef-3-em used in No. 68 is replaced with the relatively inexpensive reagent of the present invention.

[Detailed description of the invention]

"Alkyl" and "alkenyl" as used in this specification.

The terms "alkynyl", "alkynyl" and the like include straight and branched mega carbon chains unless otherwise specified. The fragment CO,- is called ``cephem'' when Z is sulfur, ``oxacephem'' when Z is oxygen, ``carbacephem'' when Z is methylene, and the birch of the vomit azabicyclo ring system. Fusangai elemental atoms have the same stereochemical form as the form of cephalosporin antibiotics currently used in a wide range of pharmaceutical applications, which is the form associated with Pharosborg 7C, which is a fermentation product.

One aspect of the present invention is 3-(fluorosulfonyl) of the following formula
Oxy-substituted cephems, oxacephems and carbacephems are provided.

(I) In the above formula (■), 2 is sulfur, oxygen, sulfoxide (-3
o, ), sulfone (Sot ), or methylenef (
-CHt-; Q is hydrogen, an amine protecting group used in cephalosporin synthesis, or the acyl group of a well-known 7-acylaminocephalosporin antagonist; and P is hydrogen, a cephalosporin Carboxy protecting groups commonly used in synthesis, cations, or physiologically hydrolyzable ester groups.

[Carboxy protecting group] is any group that readily displaces hydrogen under conditions that do not adversely affect other functional groups in the molecule. Suitable conditions for such groups and their substitution are Pr
otectillnGrowps i-calculation Organi
c 51st Lou Six (ThadoraW, Gr.
amn Author: John Wiley, New York, USA
and Sons, published in 1981], Chapter 5, No. 151~
Written on page 192 Ji! I'm in the middle of the day. Examples of carboxy protecting groups in cephalosporin/synthesis include optionally substituted lower alkyl 1 such as methyl, ethyl, trichloromethyl, trichloroethyl, tertiary bunal, methoxymethyl, methoxyethyl, acetoxymethyl, acetoxyethyl, and methane. Sulfonylmethyl; monosubstituted aralgyls such as /phenylmethyl trityl, monomethoxytritylbenzyl, l-methoxybenzyl, and 4-nitrobenzyl; silyl groups such as trimethylsilyl and t-butyldimethylsilyl; lower alkenyl 1 such as vinyl Examples include, but are not limited to, S and allyl; and aryl, such as phenyl and tolyl.

"Katana thione" is an alkali metal such as natriwam,
Lithium, and potassium: alkaline earth metals such as calcium and magnesium; ammonium; and alkylammoniums such as trimethylamine and triethylamine.

Lower alkoxycarbonyloxyalkyl groups such as etomodicarbonyloxyethyl; lower alkylcarbonyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl; and (2-oxo-1 ,3-dioxylene-4-yl)methyl group, such as (4-methyl-
Examples include, but are not limited to, 2-oxy1,3-diosol-5-ylamethyl.

Lower alkanoyl or substituted lower alkanoyl such as formyl, acetyl, chloroacetyl, S and trifluoroacetyl; aroyl or substituted aroyl such as benzoyl, 4-methoxybenzoyl, and -Nitrobenzoyl: aralkyl, substituted aralkyl,
Aralkylidenes or substituted aralkylidenes such as benzyl, diphenylmethyl, trityl nitrobenzyl,
Methoxybenzyl, and benzylidene; alkyl halides such as trichloromethyl, trichloroether,
and trifluoromethyl; alkoxycarbonyl or substituted alkoxycarbonyl; methoxycarbonyl; ethoxycarbonyl; t-butoxycarbonyl; aralkoxycarbonyl or substituted aralkoxycarbonyl; evabenzyloxycarbonyl, methoxybenzyloxycarbonyl, and nitrobenzyloxycarbonyl ; unsubstituted or If-substituted trialkylsilyloxycarbonyl or triarylsilyloxycarbonyl; and trialkylsilyl or +striarylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl.

The acyl group of the well-known 7-acylaminocephalosporin antibiotic refers to the substituent at the 7-position of the well-known cephalosporin antibiotic, and can be represented by the formula E-[(0)-. Examples of R include the following:
Not limited to these.

(a) G-CH- G' [G is a substituted or unsubstituted aryl, heterocycle, or cyclohexagenyl group, such as phenyl, thienyl,
Thiazolyl, thiadiazolyl, imidazolyl, pyridyl, tetrazolyl, 1,4-cyclohexagenyl, i6
and furyl; and the substituents of these groups are) rogene, hydroxy, amino, alkoxy, alkylamino,
dialkylamino, alkanoyloxy, carboxy,
G' may be 1 to 3 identical or different groups selected from nitro, cyano and alkoxycarbonyl;
are hydrogen, amine, monoalkylamino, dialkylamino, alkanoylamino, alkanoyloxy, carboxy, S and sulfur. ] (bJ -C- 1 OY [G has the same meaning as above, Y is hydrogen, C1-6 alkyl, yota IXC, ~, alkanoyl.] (c) G-E-CH, - [G [G and B have the same meanings as above, B is diffused or sulfur] and H [G and B have the same meanings as above, vVJ], and the door is O or 1.] Some specific examples of phosphorus antibiotic acyl groups include 2-amino-2-
Phenylacetyl, 2-amino-2-(4-(hydroxy)phenylacetyl), 2-f-enylacetyl, phenylacetyl, 2-hydroxy-2-phenylacetyl, 2-acetoxy-2-phenylacetyl, 1-tetrazoli acetyl, [(2-amino-4-thiazolyl)methoxyibano)]adecyl, phenoxy7altyl, ? and [(2-furanyl)(meth+, -diimino)]acetyl.

It should be understood that the above list only serves to explain what the term ``food'' encompasses, and is not exhaustive (and should not be construed as limiting). It is.

A preferred version of Formula I provides compounds where Z is sulfur.

Another preferred embodiment provides compounds of formula (1), where Z is methylene.

Another preferred embodiment of formula I provides all compounds in which Q is an amine protecting group. More preferably the protecting group is t-butoxycarbonyl or benzyloxycarbonyl.

Another preferred embodiment of formula I is that Q is 2-amino-2-phenylacetyl, 2-amino-2-(4-hydroxy)phenylacetyl, 2-thienylacetyl, phenylacetyl, 2- and droxy-2-phenylacetyl , 2-7cetoxy 2-phenylacetyl, l-tetrazolylacetyl [(2-amino-4-thiazolyl) (methoxyimino)]] artfl, phenoxyacetyl [(2-furanyl] (methoxyimino)] acetyl More preferably Q is selected from 2-amino-2-phenylar F-fl, 27mi/-2-(4-hydroxy)phenylacetyl, phenylacetyl, and phenoxyacetyl.

Another preferred embodiment of formula I is that P is t-butyl, benzyl,
diphenylmethyl, trityl, 4-nitrobenzyl, S
and 4-methoxybenzyl. More preferably P is t-
Choose from butyldiphenylmethyl, S and 4-methoxybenzyl.

Compounds of formula (1) are disguised by acylation of the corresponding 3-hydroxy substituted compounds of formula (2). Preferably, the 4-carboxylic group is protected by a blocking group, easily designated S. A suitable sulfonylating agent for use in this acylation is, for example, fluorosulfonic acid, or more preferably fluorosulfonic anhydride. A representative method for preparing the compound of formula (1) is shown by the following reaction scheme and is explained in more detail below.

(2) Fluorosulfonic anhydride is reacted with the starting material of formula (1) under conditions known per se for the formation of enol esters with said anhydrous reagent. Said U.S. Patent No. 4.
Conditions similar to those used for the production of the 26 tert V-t esters in No. 870.168 are suitable. This reaction is at least equimolar t on a molar basis for the reagent of formula (■).
of the anhydride, preferably in excess, for example in a 10-100 molar excess.

This is carried out by addition to a solution of the reagent of formula (1) in an inert organic solvent such as methinene chloride. A base such as a di-hindered tertiary amine (eg diimpropylethylamine) is used in approximately equimolar proportions to the anhydride reagent.

A typical method is to use a 0 to 7
It is carried out at a temperature of 8°C.

The starting materials of formula (2) are prepared in a manner well known in the art. For example, 3-hydroxycephem (f i.e. 1
Formula ■, Z = sulfur) is prepared by the method described in U.S. Pat. F produced by the method described in No. 670
L, 3-Hydroxy, 1-Carbacefem
The formula n, z=methyVn) is described in European Patent No. 211.540.
It can be manufactured by the method described in No.

3-(Fluorosulfonyl)oxy-substituted cephems, oxacephems, and carbacephems are useful intermediates in the preparation of compounds 2).

Another aspect of the present invention provides a method useful for backpassing Vc of cephems, oxacephems, and carbacephems having the following formulas:

Another aspect of the invention provides useful methods for producing cephems, oxacephems, and carbacephems having the following formulas:

C"o, p (■) In the above formula, Q, P and Z have the same meanings as defined for G, P and Z in the above formula (■). R'&1H,C,-alkenyl, C12, alkynyl, C1 ~, alkagenyl, t' !1, +6 aryl, substituted C6-16 heterocycle, and !, with the proviso that the above substituted aryl or f-acid enzymatic heterocycle is CI ~,
1-31 selected from alkyl, hydroxy, C1-1 alkoxy, halo, amino, C8-, alkyl7-mino, di-C0-, alkylamino, 2r, carboxyl, C3-, alkoxycarbonyl, and cyano. [Chivalry &'Nimotsu. Examples of heterocycles include pyridyl, imidazolyl, thiazolyl, furyl, pyrrolyl, thienyl, and isoxazole. The uninvented method is that R1 is B
%C゛2~. It is particularly useful for the production of alkenyl or C7~, alkynyl, especially compounds of 2) where R1 is C2~, alkenyl. Particularly, the method of the present invention provides cefprozil, i.e. 7β-[D-2-amino-2-(4-hydroxyphenylnoacetamide)-3-[Ca1)-
1-propen-1-yl]cef-3-em-4 carboxylic acid.

That is, the compound of formula (2) is reversed from the compound of formula (2) according to the following reaction formula.

co, p (EV) q, 2% and P are as defined above; The compound of formula RI5.
-(R”)s is reacted with organotin. However, /(l
Is it the same as the above definition? and R2 is an organic group known to be suitable for use in organotin coupling methods. For example, R1 is CI~, alkyl, such as butyl. The above reaction is performed using an inert organic bath and 1 to 1
It is carried out in the presence of 0 mol% /'d(II) or Pd(O) catalyst.

The 3-(fluorosulfonyl)oxy-substituted starting material of the above reaction scheme is produced as described above. 3-[(4-2)robenzenesulfonyl)oxacephem g and 3-[
(4-Furomobenzene)sulfonyloxy]cephem starting material #+
The corresponding oxacephem and carbacephem derivatives can also be produced in the same manner.

In the implementation of the inventive method for the infiltration of the compounds in Part 2, the aprotic organic bath medium is such that the palladium catalyst compound and the 3-sulfonyloxy compound in Part 2 are soluble, respectively. It will be exposed. 1 to 1 for the compound of formula ■
0 mole % of palladium catalyst compound is used. More catalysts within this range are used for less reactive starting materials. The RI-substituted organotin sample palladium catalyst compound and the 3-sulfonyloxy-substituted reagent of formula (1) are rapidly VC evaporated, dissolved or suspended in an aprotic bath medium. The reaction occurs spontaneously at room temperature and is complete within a few minutes, usually 10 minutes to 1 hour. Particularly in slow experimental conditions, it may not be possible to use 8 for a long reaction time of up to 2 to 3 days. Reaction times of 1 to 4 hours are usually preferred for commercial scale applications. The specific reaction time for a given synthesis, and the chosen operating scale, are determined by the starting material flow rate of Equation 1 (or for maximum production of product).
This can be confirmed by analyzing the reaction mixture WV. Thin layer chromatograph, high performance liquid chromatograph,
It can be done by using nuclear magnetic resonance, or by using the same method.

The palladium-catalyzed coupling of 3-sulfonyloxy-substituted cephems, oxacephems, or carbacephems with organotins according to the method of the invention involves the addition of non-sphinyl C-positions or (e.g., triphenylphosphine) and metal halides (e.g., zinc chloride). Their presence in the environment does not confer any advantage to the production of coupling reactions.

In the method of the present invention, the starting material of formula (1) is
-(fluorosulfonyl)oxy substituent. It can be an organic compound such as ether, exopropyl, 9-butyl, 3-pentyl, hexyl, etc.

The palladium catalyst compound is PdC11) or prtcO
) can be any of the types. Examples of catalytic compounds (PdCU) include palladium acetate, palladium chloride, palladium bromide, iodine, bis(acetonitrile).
Mention may be made of palladium dichloride, palladium bis(phenylacetonitrile) dichloride, palladium nitrate, palladium acetoacetate, palladium sulfate, and palladium oxide. Examples of penetrating Pd(O) catalyst compounds include bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetonedipalladium), and tetrakis(triphenylphosphine)palladium. Preferred palladium catalysts include palladium(n) acetate and Tris(dibenzylideneacetone)dipalladium(O
).

Aprotic solvents used in the process of the invention are 1-methyl-2-pyrrolidinone, tetrahydrofuran, acetonitrile, dimethylsulfoxide, dimethylformamide, ethers (e.g. glyme, diglyme and dioxirane), hexamethylphosphoramide, acetone, nitromethane. , nitrobenzene, and halogenated hydrocarbons (eg, methylene chloride). Preferred solvents are 1-methyl-2-pyrrolidone, tetrahydrofuran, acetonitrile, dimethylsulfoxide, methylene chloride, and dimethylformamide.

Most preferably methylene chloride or 1-methyl-2-pyrrolidinone is used. It is also possible to use solvent mixtures.

In an exciting embodiment of the invention, the 3-sulfonyloxycephem 1z3-(:(fluorosulfonyl)oxyfucephem and the organotin is R'-)! J-butyltin (7<l is 'l-nyl at C!~-7), and the palladium catalyst is palladium acetate (n)! or tris(dibenzylideneacetone)dipalladium(O), and the coupling reaction is carried out with 1-methyl-2-pyrrolidinone or methylene chloride A without added phosphine and metal halide ligand.

The process of the present invention, which involves palladium-catalyzed coupling of 3-sulfonyloxycephem with an organotin, is particularly preferred for the production of cefprozil. Z-1-propenyltrialkyl tin, a development raw material for the synthesis of cefprozil, is obtained from cis-1-bromopropene, and is an isomerically pure (>99%) compound of cis-1-bromopropene. A manufacturing method has been developed, which is discussed below.

A 500-liter plastic funnel equipped with a stirrer, a thermometer, and a glass funnel is charged with crotonic acid (51,68r, 0.6 mol; manufactured by Aldrich) and heptane (32011 IJ). The product mixture was brought to a reaction temperature of 30 DEG C. (hot water bath) under a dry sieve. Slightly: 3
4.4. 63 mol of O, 1.05 parts of the fruit (Fisher) was poured into drops for about 40 minutes.

During this time, turn off the temperature at 30℃.

Within 4-5 minutes after the addition, one crystal of the product erythro 2,3-dibromo-acid appeared. Leopard taking a cold water bath 34
The reaction temperature was maintained at °C. The mixture was brought to room temperature, stirred for an additional 16 hours, and simmered in an ice bath for 30 minutes. Colorless crystals were collected by suction filtration and diluted with heptane (2X
75 C13 and thoroughly dried at room temperature.
C1 (88%) of erythro 2,3-dibromobutyric acid was prepared.-point 87-89°C.

Overhead stirrer, temperature 6↑ and ijl danp condenser equipped, condenser tsukudato VCi net baffler
99% trienalamine (Aldrich) from 517.5 companies (371 mol, 4.13 equivalents) was charged into a flask equipped with
21.33? Erythro 2,3-dibromobutyric acid (O, 90 mol) was added in 10 uJJ portions at 5 minute intervals.

This final stage fiB + A, gas stop (bubbler) 2 and 4
He was shot because of his fever to 0 degrees Celsius. The reaction mixture was heated to 3.4 mL at room temperature.
The mixture was stirred for if; f, and then heated at 40° C. for an additional 35 hours (gas generation completed). The mixture was cooled down to room temperature and 321 red water was added. The solids were washed and dissolved. Next, 230
Beninoiso ECJ bath g (Fisher) was added, during which time the temperature was maintained at OoC. The bottom layer in the separating funnel was separated to yield 82.151 (75%) of crude cis-1-bromo-10ben. Triethylamine was recovered by pooling the aqueous phase.

The crude product was washed with saturated NaH [(/3 bath water),
Steaming at atmospheric pressure gave isomerically narrow-framed cis-1-furomobroben as an achromatic substance. Boiling point 59-60°C.

Cooled to 0~5°C, 25% of 750 Beni)
V (z) OB water bath solution was added dropwise in one and a half portions. Triethylamine was routinely recovered by separating the upper hole of the separating funnel into one layer.

The product of formula 2, in which Q is the carboxyacyl group of the well-known 7-acylaminotphalosbori/enemy substance, is itself
) IC is a useful antibiotic compound in the treatment of infections caused by Cucilia and other infectious microorganisms. However, these antibiotic compounds do not constitute part of the invention, which relates to a process for producing the antibiotic compound and a novel intermediate.

When q is B or a protecting group, the raw g'@ of 2 is converted to 2 by acylation or deproination and acyl, which is well known in the art.
is an intermediate for producing the antibiotic negative compound.

〔Example〕

The following examples demonstrate how the corresponding 3-sulfonylmakoxycef-3-M was prepared by the inventive method.
This is to explain in a physical way the method for producing R'lk-converted Cef-3-M. These examples should not be construed as limiting the scope of the invention.

Example 1 0.516 r(O
,001 mol) of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester was cooled to 0°C under a desired atmosphere. Then 0.040? (0,001 mol) of sodium hydride (60% in mineral oil) was added to generate hydrogen. The reaction mixture was stirred for 5 minutes at 0°C and
mol) of 4-nitrobenzenesulfonyl chloride was measured. The reaction mixture was incubated at 0° C. for 1 hour and stirred for 19 minutes. The medium was removed in vacuo and poured with 30M ethyl acetate. The solution was diluted with water (three times) and the organic phase was removed in vacuo to leave a foamy residue. This residue was purified by MY silica gel chromatography to yield 0.51 (71%)
The compound described above was obtained.

Minute data 'H-JVMR (CDCIs, 360Mfh):
d 8.15 (d, 2H); 7.7 (d,
211) Near, 4 6.9 (7? &, 16E)
: 6.72 (a, IB); 5.95 (dd, lf
/) ;5.3(d, l, //) :4.55s,
2H): 3.9 (d, L#): 3.58 (d.

IH).

Example 2 7-Funinoxyacetamide 3-(Z-1-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl ester Real W; 1.759 (O,0025 mol) of the product of tf11 and z -1-Frobenyrut IJ -% -Methyl tin 1.031 (O,003125 mol) and 4-nitrobenzenesulfonyl chloride 0.06 r C0,00
0.025 mol) of 1-methyl-2-virosodinone A at room temperature under a nitrogen atmosphere.
(0,00025 mol) of palladium(III) acetate was added. The reaction mixture was stirred at room temperature for 19 hours. The reaction bath was diluted with 1251 ml of ethyl acetate and the organic phase was washed with water (3 times). Acetic acid. The ethyl solution was treated with carbon and the carbon was removed by filtration through a bed of Celite. The solvent was removed in vacuo and the residue was treated with 50% ethyl acetate/%-hexane through a bed of silica gel. The crude product was Crystallization from propatool yielded 1.031? (75%) of the title compound.

Analytical data 'E-NMR (C'DCIs, 360M
Ez): δ 7.4 6.8 (m.

17H): 6.1 (by d, lH); 5.85
(dd, IH); 5.55 (groove, IH); 5.05 (
d, lE), 4.58 (a r2B); 3.43 (
d, IB); 3.25 (d, IB) Example 3 7-Funinoquine acetamide 3-[(fluorosulfonyl),rquine]-3-cephem-4-carboxylic acid diphenylmethyl ester dichloromethane (20d) The dissolved layer of 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester (2,Of, 3.8 mmol) of A was NBA at -78°C under an inert atmosphere. N-diisopropylethylamine (O, 74m
, 4.2 mmol, 1.1 equivalent jt) was added underwing over a period of 2 minutes. The resulting pale yellow bath liquid was stirred for 5 minutes and then treated with fluorosulfonic anhydride (O, 77r, 4.2
mmol, 1.1 equivalents, 1). The reaction mixture was
Stirred for 0 minutes and then stopped by mMJ of * (10 red). After warming to room temperature, the organic phase was dried over a sulfuric acid solution and the resulting solution was poured into a 70% gelatin (F21!) solution. did.

The silica gel bed was washed with ethyl acetate (l 01ti) and the collected organic fraction was concentrated to give a thorny yellow foam of 2.32. This crude product was crystallized from diethyl ether,
2.25' (96%) of the title compound was obtained as white needle crystals. Melting point 13i-132°C (decomposition).

Analysis data' If IVMR (360MHz, c″DCIs
)' 7,42 7.2 [(c, othplgz M
, 13B) ; 7.03 (apparent L
.

2B); 6.90 (d, 2H,!=7.91
1 earthquake) ; 5.97 (dd.

lE, J = 5.0.9.2Hz): 5.08(,
, d, Ill, J=5.0Hz) ;4.55 (s
, 2B); 3.83 (A of AB.

lE, /=18.511g) :3.51 (Bo
f AB, lH, J= 18.4M7, J= 1
8.5Hz).

13C' NMlt (90,5-'dEt, CDC
l5): d 168.63: 164.26:15
7.62; 156.73: 139.94; 138.4
6;138.28;129.89;128.57;12
8.51; 128.44; 128.34; 127.76
;127.25;122.55;114.71;80
．． 60; 66.98: 5g, 23; 57.33; 25
．． 58゜Elemental analysis CtsHtsFNtOa5t: Calculated value; C
', 56.17; H, 3,87: N, 4.68° Actual value: C, 55,88; #, 3.94; V, 4.56
Example 4 Paradium acetate A in 7-phenoxyacetamide-3-vinyl-3-cephem-4-carboxylic acid diphenylmethyl ester 1-methyl-2-pyrrolidinone (2 red)
II) [3,6m9.0.016 mmol, 0.1
[Children's] solution under an inert atmosphere to vinyl-tri-butyltin (5s, 4=, 0.2 mmol, 162
The mixture was treated with a lid) and stirred for 3 minutes. 7-Funinooxyacetamide 3-1: (fluorosulfonyldioxy)-3-cephem-4-carboxylic acid diphenylmethyl ester (100μ, 0.16
Mi! J mol, 1.0 kg) and the reaction mixture was stirred for 10 minutes. The reaction mixture was also diluted with ethyl acetate and washed with 2×20 red water. It was dried over magnesium oxide and condensed at ℃. The crude brown residue was purified by passing it through silica gel (WBR, 951r) for 7 hours. First, the residual tin was removed using dichloromethane (507). , and then treated with 10% ethyl acetate in dichloromethane (75m).Iso-sardination gave 74.8~(85%) of the title compound as a white solid.

Partial blindness theta'H4VtWl< (3b O, WE m JCDC
jls): δ7.42-7.23(compLax
tn, l211): 7.04-6.92
(comp ax fable, 211); 6.91 (d
, IB, ! =7.8211g) ;5.90(
dd, lH, J=4.9.9.2Bg): 5.4
2 (d, IHI) = 17.6f! gno; 5.
26 (d, L&, J=1 1.2Bz); 5.0
2 (ti, 1#, !=4.9Bg);4.
55 (s, 2B);:3.6 2 (, (Of
-IB, IE, J=1 7.7#
g]; 3.4 6 (B of AB, l#
, J=17.7#g).

"C, 'vMRC90, 5Mf/g, CDC'ls)
: a l 68.66; 164.19:
161.00; 156.82; 139.28; 139.
01;131.79;129.77;128.51;1
28.39; 128.16: 128.04; 127.7
2; 127.54; 127.01; 126.4
8; 122.32; 118.07; 114.6
9;79.37:67.01:58.47:57.2
7; 24.09゜Working Example 5゜7-Phenoxyacetamide-3-(Z-1-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl ester Palladium acetate (9) in dichloromethane (2-) [3
, 6■, 0.016 mmol, 0.1 child] VZ-1
-propenyl-tri-butyltin (66,2my
, 0.2 mmol.

1.2 equivalents] under an inert atmosphere and stirred for 3 minutes.

The resulting dark suspension was then diluted with 7-phenoxyacetamido-3-[(fluorosulfonyl)oxy]-3-cephemu-4-carboxylated diphenylmethyl ester (10
0,0~.

The reaction mixture was stirred for 10 minutes. The reaction mixture was diluted with dichloromethane and washed with water (IXIO red). Youminzhu was dried over porcelain magnesium and purified by filtration on silica gel (Tarpreux R. Cress, 951J#'L bed). First, dichloromethane (
Residual tin was removed with 50 mA) and then treated with dichloromethane (50 mA). Extremely 80.41i! Evening (8
9%) had a tan-yellow-like proboscis.

Product 'ff: Then recombined from in-10biru alcohol to give 62:1 (sc+%) of a white solid. Melting point 103-104°C8 Qualitative data 1H NortR (360MHz, C1) CIs)
: δ 7.4 1-6.9 0<, compta
zM, 1711) ;6. lo(d, 1#, /=11.
71it); 5.90',,dd,IB
, J=4.5. 9. LHgno; 5.56 (m,
IH); 5.07 (d, IH, J=4.5#g)
:458(a, 2B) : 3.47 <A of
AB, 111. J=17.5#g):3.28(B
of, 4H, LH, J=L7.511g); 1.4
1(dd, 31)', J-1,7,7,1Hg).

13CNMR (90,5ilf#z, CDC13)
: δ 1 6 8.6 3 ; 164.28
; l 61.28 ; 156.83 ; l 39
．． 42; 139.10; 130.33; 129.80
;129.74;128.45;128.28;128
．． 08;127.79;127.81;127.18
;125.88;122.37;114.74: 7
8.99; 67.06; 58.45; 57.55
;2850゜Example 6゜7-Funinoxyacetamide 3-[4-furophenylsulfonyl 9oxy]-3-cephem-4-carboxylic acid/phenylmethyl ester US Pat. No. 3,985.737 The title compound was prepared by a modification of the platform method described. 5. Acetoni I-'
A solution of 0.517 (0,001 mol) of 7-acetamide j-hydroquine-3-cephem-4-trifluorine-dispersed diphenyl methyl ester in J.L. was cooled to 0° C. under a nitrogen atmosphere. Then 0.03Of(O,00
1 mol) of atrium hydride (mineral oil r-P 80%) was added to generate an aqueous solution. Reaction mixture bz'vo''C was heated for 5 minutes and 0.229 f (O,009 mol) of 4
- Furomobenzenesulfonyl chloride was introduced. The cooling mixture was removed, and the reaction mixture was kept at a temperature of 19:00.

The reaction mixture was treated with yp and treated with P solution. The solvent was then removed to leave a Form IA residue. This residue is assembled from 1-proper tool (13
98r (54%) of the listed compound was removed.

Qualitative data Iu xV, 4fR (tDcls, 36 QAt#
g): δ7.5 (d, 211); 7.4 (d,
2'& (1), 7.4-6.9 (嘱, 16B8 6.79
(s, 111), 5.9 < dd, IB), 5.1(
d, LH), 4.55 (s, 2B): 3.85
<d, LH), 3.5(C[.

lH).

Example 7 Preparation of Example 6 of 7-funinoxyacetamide 3-(,Z-1-7'ropenyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (L184f (0,00025 mol)) Object, 0.103f (O, 0003215 morn, i?
-1-propenyl-tri-butyltin, and 0
．． To a mixture of 0.0064r (O,000025 mol) of 4-70 mobenzenesulfonyl chloride in 12.5Wj of 1-methyl-2-pyrrolidinone was added 0.006 t (O,000025 mol) of Palladium acetate (9) was added. The reaction mixture was stirred at room temperature for 20 hours. High pressure liquid chromatography of the reaction mixture (I
IPLC) The quality showed a peak of the title compound having the same characteristics as the positive sample. HPLC surface number of this peak. It was 21.2%.

Practical Example 8 7-Funinoxyacetamide 3-(Z-1-)ylopenyl)-3-cephem-4-carboxylic acid diphenylmethyl ester dichloromethane (2-) or 1-methyl-2-pyrrolidinone (2-) ) in tris(dibenzylideneacetone)
Dipalladium (14.6, 0.016 mmol, 0.
1 equivalent'jjL) solution of z-1-probenyrut in an inviscid atmosphere! J-s-butyl tin (66,2■, 0.
2 mmol, 1.2 equivalents jt). Formation bath g was then treated with 7-funinoxyacetamide 3-[(fluorosulfonyl)oxy]-3-cephemu 4-carboxylic acid diphenylmenal ester (100.0 ml).

0.16 mlJmol, 1-0 i1) and the reaction mixture was run on HP Lt'. The reaction experiment in dichloromethane A took longer than 171 VC for 3 hours, but the reaction experiment in -Menal-2-pyrrolidinone completed within 8 hours. Yield of desired product > 9 as determined by HPLC
8':'o. The JVMR fraction at 360 MEt of the products from both reaction warmers was consistent with the title compound.

Example 9 7-Funinoxyacetamide 3-(Z~1-probel)-3-cephem-4-carboxylic acid diphenylmethyl ester; by using tris(dibenzylideneacetone)dipalladium (υ): 0.175y (O,00025 7 l) of the product of Example 1 and 0.099r (O,0QO3 7 l) of z-1-bo
To a mixture of 1.0 red 1-methyl-2-pyrrolidinone A of bunaltin, nitrogen 4
O, t) 14 ? at room temperature under air. (f)l)OOQ2
5 mol) of tonos(dibenzylideneacetone 7'
"U/Tsum (O) was added to 1, and the reaction mixture was heated to 17 at room temperature.
Stir for 1 hour. The reaction mixture was diluted with ethyl acetate and the organic fraction was precipitated twice with -λ. The ethyl acetate bath was treated with carbon, and the carbon was filtered through a light bed. After removing the liquid, there is a foamy residue. This residue was subjected to Mb analysis using gel chromatography.
The title compound of 06(1 (44%)) was obtained. 8j magnetic resonance spectrum was consistent with the title compound.

lolN gAI 10゜7-(benzyloki7carbonylamino)-3-fluorosulunyloxy-1-carba(l-fthia)-3-
Cefem-4-Carvone ME-phthyl ester methylene chloride (665μ!, 1.36 Mp3i'ft of fluorosulfonyl anhydride in 0.906 mmol 9,
7-(benzyloxy7) in methylene cucolide (5)
carbonylamino)-3-hydroxy-1-carba(1
-Tethia 9-3- with femu 4-carboxylic acid C-phthyl ester (3521119,0,906 mmol) and diisopropylethylamine (158 μJ, 0.90
6 mmol) was added dropwise to a yukata (Co/acetone bath) with stirring. This f6 liquid was heated to 0.25℃ at -78℃.
The solution was stirred for 0.25 hours, the water bath removed and stirring continued for 0.25 hours. Wash this solution three times with water and then
dried on a humidifier. Remove the heating medium to thin the viscous gum-like substance and add methylene chloride/acetone (95,1
5) on Sin to give the title compound (130 I!ly, yield 90 r'o) as a viscous gum.

This was crystallized from ethyl acetate/hexane to give colorless crystals (56~). - point 118'c (decomposition data 'HNMR(C'l)C'! 33, 3 U Oi Hz: t37.35 (5B, s), 5.37 (1#
, tn), 5.22 (1#, m), 5.11 (2B
.

S), 3.87 (IE, mba 2.65 (2B, m
), 2.13 (IN, m), 1.68 (1#,
1.53 (9B, x) to m.

Mass-spectrum: (positive a:t:/FAB, hOBA)
m/z471(J(±1).

Waiting +: Applicant Pristoo My Chords Squiff Casono 1° Knee Agent Masu-shi-suke Kumasu-shi-ryu Approved Masu-shi Akira Mizuno

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Z is sulfur, oxygen, sulfoxide, sulfone,
or methylene; Q is hydrogen, an amine protecting group commonly used in the synthesis of cephalosporin compounds, or the well-known 7
- an acyl group of an acylaminocephalosporin antibiotic; and P is hydrogen, a carboxy protecting group commonly used in the synthesis of cephalosporin compounds, or a physiologically hydrolysable ester. 2. The compound according to claim 1, wherein Z is sulfur. 3, Q is phenoxyacetyl, phenylacetyl, 2-
Amino-2-phenylacetyl, 2-amino-2-(4
-hydroxyphenyl)acetyl, and benzyloxycarbonyl. 4. The compound according to claim 1, wherein P is t-butyl, diphenylmethyl, or 4-methoxybenzyl. 5,7-phenoxyacetamido-3-[(fluorosulfonyl)oxy]-cef-3-em-4-carboxylic acid. 6,7-phenoxyacetamido-3-[(fluorosulfonyl)oxy]cef-3-em-4-carboxylic acid diphenylmethyl ester. 7,7-Phenoxyacetamido-3-[(fluorosulfonyl)oxy]cef-3-em-4-carboxylic acid 4
-Methoxybenzyl ester. 8,7-phenylacetamido-3-[(fluorosulfonyl)oxy]cef-3-em-4-carboxylic acid. 9,7-phenylacetamido-3-[(fluorosulfonyl)oxy]cef-3-em-4-carboxylic acid diphenylmethyl ester. 10,7-phenylacetamido-3-[(fluorosulfonyl)oxy]cef-3-em-4-carboxylic acid-
4 methoxybenzyl ester. 11,7-[2-amino-2-[(4-hydroxyphenyl)acetamide]]-3-[(fluorosulfonyl)oxy]-cef-3-em-4-carboxylic acid. 12,7-[2-amino-2-[(4-hydroxyphenyl)acetamide]]-3-[(fluorosulfonyl)oxy]-cef-3-em-4-carboxylic acid diphenylmethyl ester. 13,7-(2-amino-2-[(4-hydroxyphenyl)acetamide]]-3-[(fluorosulfonyl)oxy]-cef-3-em-4-carboxylic acid-4-methoxybenzyl ester. 14 , Z is methylene. 15,7-[(benzyloxycarbonyl)amino]-
3-[(fluorosulfonyl)oxy]-1-carba(
1-dethia)-3-cephem-4-carboxylic acid t-butyl ester. 16. Formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Z is sulfur, oxygen, sulfoxide, sulfone,
or methylene: Q is hydrogen, an amino protecting group commonly used in the synthesis of cephalosporin compounds, or the surrounding 7
- is the acyl group of the acylaminocephalosporin antibiotic; P is hydrogen, a carboxy protecting group commonly used in the synthesis of cephalosporin compounds, or a physiologically hydrolyzable ester; and R^1 is H, C_2_ ~＿
6 alkenyl, C_2_~_6 alkynyl, C_2_~
_6 alkadienyl, C_6_~_1_0 aryl,
Substituted C_6-C_1_0 aryl, cyclotrogen, and substituted heterocycle (however, the substituted aryl or substituted heterocycle is C_
selected from the group consisting of 1_-_3 alkyl, hydroxy, C_1_-_3 alkoxy, halo, amino, C_1_-_3 alkylamino, di-C_1_-_3 alkylamino, nitro, carboxyl, C_1_-_3 alkoxycarbonyl, and cyano group A method for producing a cephalosporin antibiotic containing 1 to 3 substituents), which has the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Q and P are as defined above; L is selected from the group consisting of fluorosulfonyloxy, 4-nitrobenzenesulfonyloxy, and 4-bromophenylsulfonyloxy] with the formula R^1
-S_n-(R^2)_3 organotin compound [where R^1 in the formula is as defined above; R^2 is an organotin compound known to be suitable for use in the organotin coupling method. Pd(II) or Pd(O) in an inert aprotic solvent with 1 to 10 mol% of Pd(II) or Pd(O)
A method characterized by carrying out the reaction in the presence of a catalyst. 17. The method of claim 16, wherein R^1 is C_2_-_6 alkenyl. 18. Claim 16, wherein L is fluorosulfonyloxy.
Method described. 17. The method according to claim 16, wherein 19, L is 4-nitrobenzenesulfonyloxy. 17. The method according to claim 16, wherein 20, L is 4-bromobenzenesulfonyloxy. 21. The method according to claim 16, wherein the Pd(II) catalyst is palladium(II) acetate. 22. The method of claim 16, wherein the Pd(II) catalyst is palladium dichloride. 23. The method according to claim 16, wherein the Pd(II) catalyst is bis(acetonitrile)palladium(II) dichloride. 24, the organic tin compound is vinyltributyltin, Z-1-
17. The method of claim 16, wherein the compound is selected from the group consisting of propenyltributyltin, 2-methyl-1-propenyltin, 1-propynyltributyltin and (4-methoxyphenyl)tributyltin. 25. The method according to claim 16, wherein the aprotic solvent is 1-methyl-2-pyrrolidinone, methylene chloride, or acetonitrile. 26. The method of claim 16, wherein the reaction is carried out in the absence of added phosphine ligand and metal halide. 27. The method of claim 16, wherein the Pd(O) catalyst is tris(dibenzylideneacetone)dipalladium.